The long-term practice of aerosol therapy during mechanical ventilation is continually evolving due to its unacceptable poor efficiency. This inefficiency partly results from the high losses of drugs in the ventilation components and the extrathoracic airways. The type of ventilator, mode of ventilation, type of patient interface, the aerosol generator and its configuration, aerosol particle size and breathing parameters have been identified as factors that influence the efficiency of aerosol therapy during ventilation.
High losses in the ventilation components and the extrathoracic airways could be avoided by optimizing the size of the aerosol to produce low aerosol losses and acceptable drug dose delivered to the lungs. Condensational growth of the submicrometer aerosols within the airways is one approach to prevent exhalation of the aerosol and is achieved either by the co-administration of supersaturated humidified air (enhanced condensational growth, ECG), as used in high flow therapy, or by addition of a hygroscopic excipient to the aerosol formulation, which enables growth using the natural humidity of the respiratory system (excipient enhanced growth, EEG). Studies of such techniques using steady inhalation flow conditions appeared to produce high emitted and lung doses, however the effects of realistic breathing profiles are known to create significant challenges for effective aerosol delivery during ventilation therapies. Thus, the benefit of condensational growth techniques during realistic breathing needs to be determined. A significant challenge is to overcome the losses of drug aerosol during exhalation. Pulsating aerosol delivery (aerosol delivered by pulsating aerosol generation) during the inhalation portion of the breathing cycle is one approach to minimize exhalation losses. Pulsating aerosol drug delivery has been used for numerous applications such as intermittent positive pressure breathing during ventilation and drug delivery to the sinuses. However, the effectiveness of this method has been controversial and not been apparent in all applications.
Mechanical ventilation is frequently used for cases of respiratory insufficiency that may arise from acute lung injury, acute respiratory distress syndrome, pulmonary disease, and cardiac failure. The two primary forms of mechanical ventilation are invasive and non-invasive. Both approaches are intended to deliver gases and frequently pharmaceutical aerosols to the lungs in a safe and efficient manner, with the goal of maintaining appropriate blood oxygen and carbon dioxide levels. Invasive mechanical ventilation may employ an endotracheal tube (ETT), tracheostomy tube, or laryngeal airway mask inserted to bypass the extrathoracic airways and provide access to the lungs. Non-invasive ventilation (NIV) delivers respiratory support with an interface at the nose and/or mouth. Common forms of non-invasive ventilation include low flow nasal cannula, non-invasive positive pressure ventilation with oral and/or nasal interfaces, and humidified high nasal flow cannula. Common problems related to mechanical ventilation include (1) CO2 re-breathing of expired gas, (2) difficulty in weaning from invasive mechanical ventilation, (3) damage to the airways due to pressure and over inflation, especially for stiff and diseased lungs, and (4) poor delivery efficiency of pharmaceutical aerosols through the ventilator circuit. These issues are described in more detail below.
Mechanical ventilation seeks to supply oxygen and remove CO2 from the blood. Both processes are necessary for successful mechanical ventilation. Too much CO2 in the blood leads to hypercapnia, which is associated with tachypnea, dyspnea, reduced neural activity, raised blood pressure and eventually death. At CO2 levels of approximately 3%, moderate respiratory stimulation to hypercapnia begins to occur. In mechanical ventilation systems there is an overlap region between the inspiratory and expiratory lines. Within this overlap region, also termed ventilator dead space, a portion of the expired breath is held and then re-breathed on the next inhalation. This re-breathing can increase the CO2 concentration of the inspired air potentially leading to hypercapnia. Moreover, mixing of the expired air with the air in the inspiratory line can increased the re-breathing of CO2. Current methods to prevent re-breathing CO2 include implementing a bias flow on the system to flush out CO2 [4] and the use of dual lumen ETTs. However, bias flow may result in elevated ventilation flow rates, which may be injurious to the airways. Dual lumen ETTs complicate the system and would be difficult to apply to the very narrow airway passages of neonates.
Weaning from invasive mechanical ventilation is a very difficult process that frequently fails, requiring re-administration of ventilation support. The readiness for weaning from the ventilator is typically assessed by the evaluation of spontaneous breathing effectiveness over a period of 30 to 120 minutes, often while still connected to the ventilator. Spontaneous breathing is also encouraged by most ventilator systems in order to maintain the muscle tone and ventilatory drive of the patient. As a result, the mechanical ventilation system should make spontaneous breathing as easy as possible. However, high flow resistance of the ventilatory circuit provides an additional hurdle to spontaneous breathing. The resistance in the ventilatory circuit and its effect on spontaneous ventilation have not been previously considered.
Mechanical ventilation may cause damage to the airways by over-pressurizing or over-inflating the alveolar airspace (barotrauma and volutrauma). This can lead to airway inflammation, increased lung resistance, decreased compliance, and difficulty with continued ventilation. Frequent opening of collapsed alveoli can also lead to inflammation. Positive end-expiratory pressure (PEEP) is typically set to maintain open alveolar airspace throughout the breathing cycle. The cyclic pressure and volume peak values superimposed on PEEP can induce barotrauma and volutrauma. Ideally, the required volume flow should be delivered to the lungs with a minimum peak pressure value above the PEEP setting. To control peak pressures, current ventilators have a pressure-based delivery mode and/or limits in place to avoid pressures above a maximum value. For high resistance systems, limiting the pressure also limits the flow rate that can be achieved. Lung injury can be reduced by delivering a desired amount of gas flow (volume) with a minimum pressure rise above the PEEP setting. This is especially important in cases of diseased and/or inflamed lungs where compliance is reduced and resistance is increased.
For conventional aerosol drug therapy during NIV, drug delivery efficiencies through the ventilation circuit are typically <1-10% in adults and children based on in vitro experiments and 1-6% in vivo evidence. Differences between in vitro and in vivo estimates are often due to the absence of humidified conditions and the absence of an exhaled fraction in the in vitro experiments. Previous studies of aerosol delivery efficiency with nasal cannula interfaces have focused on low flow rates in adult and infant models. Bhashyam et al. considered aerosol delivery from a mesh nebulizer (Aeroneb Solo, Aerogen Limited, Galway, Ireland) through infant, pediatric, and adult nasal cannulas at an inspiratory flow rate of 3 liters per minute (LPM) with a heated and humidified system. Drug depositional losses in the connectors, tubing, and cannula resulted in a total output that ranged from 19-27% of the initial dose when simulated inhalation was included in the system. Ari et al. considered aerosol delivery from the Aeroneb Solo device through an Optiflow (Fisher and Paykel, Irvine, Calif.) pediatric nasal cannula at flow rates of 3 and 6 LPM with oxygen or heliox. The maximum cannula aerosol drug delivery efficiency of approximately 10% occurred with a flow rate of 3 LPM and was decreased significantly with the use of the higher flow rate and heliox.
Respiratory drug delivery during mechanical ventilation with an endotracheal tube (invasive mechanical ventilation) is known to be inefficient based on in vitro and in vivo studies. Lung drug delivery efficiency values for pressurized metered dose inhalers and nebulizers administered during ventilation are typically less than 10% during all forms of mechanical ventilation. Vibrating mesh nebulizers have increased aerosol delivery efficiencies to values in the range of 10-25% based on in vitro studies of invasive ventilation. Inhalation triggering of a vibrating mesh nebulizer coupled with aerosol delivery during a portion of the inspiration flow further increased delivery efficiency to values as high as 60%. However, one disadvantage of breath activated mesh nebulizers is the relative cost and complexity of the system compared with other aerosol delivery technologies.
Previous studies have observed high aerosol drug losses during mechanical ventilation in the aerosol source adapter, connectors, and endotracheal tube (ETT). Based on these high depositional losses, it can be concluded that current commercial ventilator circuits are not designed for the efficient delivery of aerosols. A practical and cost effective method to improve aerosol delivery efficiency during mechanical ventilation is to redesign the ventilator circuit components responsible for high aerosol deposition losses in ways that also have a positive effect on gas delivery. In U.S. Pat. No. 7,290,541, Ivri et al. suggest that low angles at ventilator circuit transition points (<15°) can be used to improve aerosol delivery during mechanical ventilation. However, these low angles typically require additional lengths of ventilator tubing and/or line positioning which may not be practical in critical care settings. Increasing the tubing length will also increase aerosol loss by sedimentation and may increase ventilator dead space and CO2 re-breathing. In most practical aerosol delivery systems, the aerosol stream is required to change direction by an angle of 90° or more and the conduit size changes diameter at least once. In some systems, multiple changes in direction and conduit size are required. For example, an invasive mechanical ventilation system may include a T-connector, Y-connector, and endotracheal tube that curves through the extrathoracic airways. As the aerosol moves through the Y-connector, there is a minimum 90° change in direction followed by an approximately 90° change in direction in the endotracheal tube. As a result, the aerosol stream has changed direction by 180°, not including additional changes in direction in the connective tubing as well as changes in conduit size.